Article Text

Download PDFPDF

Changes in neovascular activity following fixed dosing with an anti-vascular endothelial growth factor agent over 52 weeks in the phase III VIEW 1 and VIEW 2 studies
  1. Darius M Moshfeghi1,
  2. Desmond Thompson2,
  3. Namrata Saroj2
  1. 1Stanford University School of Medicine, Palo Alto, California, USA
  2. 2Regeneron Pharmaceuticals, Inc, Tarrytown, New York, USA
  1. Correspondence to Dr Darius M Moshfeghi, Stanford University School of Medicine, Palo Alto, California, USA; dariusm{at}stanford.edu

Abstract

Background/aims To understand changes in disease activity as assessed by leakage and retinal fluid status in patients with neovascular age-related macular degeneration (nAMD) receiving fixed dosing with an anti-vascular endothelial growth factor (anti-VEGF) agent.

Methods In the phase III VIEW 1 (NCT00509795) and VIEW 2 (NCT00637377) studies, eyes with nAMD were treated with intravitreal aflibercept or ranibizumab. Independent, masked reading centres determined the presence/absence of leakage (fluorescein angiography) and retinal fluid (optical coherence tomography) at baseline, week 24 and week 52. In this integrated, post hoc analysis of the VIEW studies, the relationship between leakage/fluid status and best-corrected visual acuity (BCVA) was assessed. The impact of baseline lesion type (predominantly classic (PC), minimally classic (MC), occult) was also evaluated. Data from all treatment groups were pooled.

Results 2373 eyes were included in this analysis. At baseline, 95.4% of eyes presented with both leakage and fluid. By week 52, leakage and fluid were present in 16.0% of eyes. Mean BCVA gains at week 52 were numerically greater in eyes without leakage and fluid versus eyes with both leakage and fluid (10.3 vs 9.2 letters). At week 52, 11.6%, 15.3% and 20.1% of eyes with PC, MC and occult lesions, respectively, had both leakage and fluid present.

Conclusion In this post hoc analysis, fixed dosing with an anti-VEGF agent over 52 weeks eliminated disease activity (absence of both leakage and fluid) in most eyes. The effect of anti-VEGF treatment on leakage/fluid status favoured PC versus occult lesions.

  • retina
  • macula
  • degeneration
  • clinical trial
  • treatment medical

Statistics from Altmetric.com

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Introduction

Neovascular age-related macular degeneration (nAMD) is the leading cause of blindness among people aged ≥50 years in the Western world.1 Overexpression of vascular endothelial growth factor (VEGF) has been observed in eyes with nAMD.2 Multiple factors have been attributed to this overexpression: oxidative damage, complement-mediated inflammation, environmental factors and genetic polymorphisms.3 Elevated VEGF levels lead to endothelial cell activation, proliferation and migration, resulting in angiogenesis and vascular leakage in the retina.2 3 These processes bring about the development of choroidal neovascularisation (CNV) and fluid accumulation, hallmarks of the pathogenesis of nAMD that converge to result in vision loss.2 3

The introduction of anti-VEGF agents has transformed the management of nAMD from therapies preventing vision loss to those resulting in visual gains in most patients.4–6 However, anti-VEGF treatment has been shown to play a greater role in preventing the progression of disease than in regressing disease.7 As such, fixed and continuous dosing of eyes with nAMD is essential for maintaining optimal control of disease activity and vision.8

Fluorescein angiography (FA) and optical coherence tomography (OCT)9 have provided physicians with the tools to diagnose disease and manage treatment course based on the response to anti-VEGF therapy.10 OCT has rapidly replaced FA, which can be arduous on the technician and patient and cannot feasibly be performed as frequently as OCT. FA and OCT are complementary modalities: FA provides details on CNV, and OCT primarily provides information on fluid status. To understand the concurrent changes in disease activity assessed by the two imaging modalities, a post hoc analysis of two large clinical trials, VIEW 1 and VIEW 2, was conducted.

Methods

Study design

VIEW 1 (NCT00509795) and VIEW 2 (NCT00637377) were two similarly designed prospective, multicentre, double-masked, active-controlled, parallel-group, randomised clinical trials conducted globally.11 12 The design of the VIEW studies has been previously described.11 Each clinical site’s respective institutional review board/ethics committee approved the study. Briefly, patients were eligible if they were ≥50 years of age with active subfoveal CNV lesions of any subtype secondary to age-related macular degeneration, including juxtafoveal lesions affecting foveal integrity.11 Eyes were required to have a best-corrected visual acuity (BCVA) score between 73 and 25 ETDRS letters in the study eye (20/40 to 20/320 Snellen equivalent).11 The key exclusion criterion was any previous treatment for nAMD. All patients provided written informed consent.11 Eligible patients were randomised (1:1:1:1) to one of four treatment groups for the first 52 weeks: (1) 0.5 mg intravitreal ranibizumab every 4 weeks (Rq4), (2) 2 mg intravitreal aflibercept injection (IAI) every 4 weeks (2q4), (3) 0.5 mg IAI every 4 weeks (0.5q4) and (4) 2 mg IAI every 8 weeks following three initial monthly injections (2q8).11

Evaluation of BCVA and time-domain OCT (TD-OCT) were performed at every study visit.11 FA was performed at baseline, week 24 and week 52.11 Independent, masked readers at the Digital Angiography Reading Center (New York, New York, USA) determined the presence or absence of leakage on FA. Similarly, masked readers at Duke Reading Center (VIEW 1, Durham, North Carolina, USA) and Vienna Reading Center (VIEW 2, Vienna, Austria) determined the presence or absence of retinal fluid. TD-OCT image grading was harmonised between the Duke and Vienna OCT reading centres.

Study population

Eyes with available data on leakage and retinal fluid status at baseline, week 24 and week 52 were included in this post hoc analysis. Based on their anatomic status, eyes were categorised into four subgroups: (1) both leakage and fluid present; (2) leakage present, fluid absent; (3) leakage absent, fluid present; and (4) both leakage and fluid absent.

Outcome measures

The primary focus of this post hoc analysis was to evaluate the status of leakage on FA and retinal fluid on TD-OCT at baseline, week 24 and week 52. Mean change in BCVA based on leakage and fluid status was assessed. The presence/absence of overall retinal fluid, as well as intraretinal and subretinal fluid, was examined. The impact of lesion type (predominantly classic (PC), minimally classic (MC), occult) and the correlation between leakage on FA and central retinal thickness (CRT) were also evaluated.

Statistical methods

Data from both VIEW 1 and VIEW 2 were integrated, as the outcomes across studies were consistent. Additionally, all treatment and dosing groups were combined. Observed data at each time point were analysed. The differences in the change in BCVA score from baseline between the four subgroups were assessed using t-tests. Logistic regression was used to assess the dependence of the ORs on lesion type. Linear correlations were used to assess the degree of association between leakage and CRT. All results nominally significant at the p<0.05 level are indicated. Analyses were performed using SAS V.9.4.

Results

Of the 2457 patients randomised to the two VIEW studies, 2373 had data available on leakage and retinal fluid status at baseline, week 24 and week 52 and were included in this post hoc analysis.

Evaluation of leakage and fluid status

At baseline, 95.4% of eyes presented with both leakage on FA and overall retinal fluid on TD-OCT compared with <0.1% with neither leakage nor fluid (figure 1A). By week 24, this proportion decreased to 27.8%, and eyes with neither leakage nor fluid increased to 34.7%. The corresponding proportions following 52 weeks of fixed dosing were 16.0% and 49.1%, respectively. At week 24, the proportion of eyes with leakage present and fluid absent was 23.2%, and those with leakage absent and fluid present was 14.3%. These proportions remained largely similar at week 52 (19.1% and 15.7%, respectively).

Figure 1

Leakage and (A) overall retinal, (B) intraretinal, and (C) subretinal fluid status at baseline, week 24 and week 52. Full analysis set. Observed data.

Assessment by fluid type demonstrated that 61.0% of eyes presented with both leakage and intraretinal fluid at baseline, which decreased to 8.3% by week 52 (figure 1B). At week 52, 54.2% of eyes had no evidence of leakage and intraretinal fluid. Similarly, 80.7% of eyes presented with both leakage and subretinal fluid at baseline, which decreased to 10.1% by week 52 (figure 1C). At week 52, 59.4% of eyes had neither leakage nor subretinal fluid.

Based on leakage and overall retinal fluid status at week 24, mean BCVA gains from baseline to week 24 were 9.9 letters in eyes with both leakage and fluid absent, 8.3 letters in eyes with leakage absent and fluid present, 8.6 letters in eyes with leakage present and fluid absent, and 7.4 letters in eyes with both leakage and fluid present (table 1). Corresponding mean BCVA gains at week 52 based on leakage and fluid status at week 52 were 10.3, 8.5, 8.6 and 9.2 letters, respectively. A statistically significant difference in the mean change in BCVA between baseline and week 24 was observed between eyes with leakage and fluid present compared with eyes without leakage and fluid, irrespective of retinal fluid type (overall, intraretinal or subretinal) (table 1). Statistical significance was not observed at week 52.

Table 1

Mean change in best-corrected visual acuity from baseline by leakage and retinal fluid status at weeks 24 and 52

Evaluation of leakage and fluid by lesion type

Leakage and fluid status were further evaluated by lesion type (PC, MC or occult), as classified by the independent reading centre. At week 52, 11.6%, 15.3% and 20.1% of eyes with PC, MC and occult lesions, respectively, still demonstrated the presence of both leakage and overall retinal fluid (figure 2A). The proportion of eyes with an absence of both leakage and fluid at week 52 was highest for PC lesions (56.4%) followed by MC lesions (49.1%) and occult lesions (43.8%). Using the subgroup of eyes with occult lesions as a reference, eyes with PC lesions exhibited a higher odds of having both leakage and overall retinal fluid absent (OR, 1.66; 95% CI 1.33 to 2.08). Similar observations favouring PC lesions were noted when analysed by intraretinal (figure 2B) and subretinal (figure 2C) fluid status.

Figure 2

Leakage and (A) overall retinal, (B) intraretinal, and (C) subretinal fluid status at week 52 by baseline lesion type. Full analysis set. Observed data.

Mean changes in BCVA between baseline and week 52 by baseline lesion type and leakage/overall retinal fluid status at week 52 are provided (figure 3). In all categories of leakage and fluid status, visual gains were numerically in favour of eyes with PC lesions. Among eyes with both leakage and fluid present, those with PC lesions gained an average of 4.9 letters between baseline and week 52 relative to eyes with occult lesions.

Figure 3

Mean change in best-corrected visual acuity at week 52 by baseline lesion type and leakage and overall retinal fluid status at week 52. Full analysis set. Observed data. BCVA, best-corrected visual acuity.

Leakage and CRT

There were weak correlations between leakage (as measured on FA) and CRT at both baseline (correlation coefficient, 0.14; 95% CI 0.10 to 0.18) and week 52 (0.16; 95% CI 0.11 to 0.2), with increased CRT suggesting the presence of fluid. There were also weak correlations between the change from baseline for leakage status and CRT at week 52 (0.21; 95% CI 0.17 to 0.25).

Discussion

The recurrence of disease activity in eyes with nAMD is evidenced by reductions in vision, leakage on FA and the presence of retinal fluid on OCT. In the VIEW 1 and VIEW 2 studies, a fixed anti-VEGF dosing regimen for 52 weeks generally resulted in visual gains.11 12 To understand the changes in disease activity during ongoing anti-VEGF treatment, we examined leakage and retinal fluid status.

The results from our analysis demonstrated that despite fixed and prolonged anti-VEGF treatment, some eyes continued to exhibit ongoing disease activity, as demonstrated by the presence of both leakage and overall retinal fluid in 16.0% of eyes at week 52. We also found the effects of fixed dosing with an anti-VEGF agent to be cumulative, as a longer duration of treatment resulted in a greater proportion of eyes (34.7% at week 24 vs 49.1% at week 52) with no evidence of disease activity (absence of both leakage and retinal fluid). Since both intraretinal and subretinal fluid tended to resolve over 52 weeks, the drying effect of anti-VEGF treatment appeared to be independent of fluid location.

Visual acuity gains were seen in all leakage/fluid status subgroups. A statistically significant difference in the change in visual acuity between eyes with and without disease activity, as determined by both FA and OCT, was observed at week 24. Although a numerical advantage was observed at week 52, statistical significance was not reached. Together, these results indicate that eyes administered prolonged, fixed anti-VEGF treatment may continue to experience improvements in vision, even in the presence of leakage on FA and/or retinal fluid on OCT.

The effect of anti-VEGF treatment on leakage/retinal fluid status favoured PC versus occult lesions, as eyes with PC lesions had a higher odds of being without leakage and overall retinal fluid at week 52 than eyes with occult lesions. This also translated to a greater mean gain in BCVA between baseline and week 52 for eyes with PC versus occult lesions (+4.9 letters). Although we observed a rank ordering for the proportion of eyes without leakage and retinal fluid (PC>MC>occult), an inconsistent ordering by lesion type was observed in a post hoc analysis of the VIEW studies that evaluated the early (week 12) persistence of fluid.13 The differences between the two post hoc analyses of VIEW 1 and VIEW 2 could be attributable to the earlier timepoint utilised in the early persistent fluid analysis (week 12) relative to the current analysis (week 52) or may simply represent a lag in the cumulative effect of multiple anti-VEGF injections.

The subgroup of eyes with leakage absent and fluid present could be explained by sequestration of retinal fluid in the absence of ongoing leakage. Additionally, malfunction of the retinal prigment epithelium could result in an absence of active CNV on FA and presence of retinal fluid on OCT.14 Furthermore, the subgroup of eyes with leakage present and fluid absent imply a lack of absolute concurrence between leakage and retinal pigment epithelial pump activity. Likely, this probably represents staining and not leakage. This was especially evident in the 24.7% of eyes with occult lesions where leakage was present on FA but overall retinal fluid was absent on OCT at week 52. Dual management with both FA and OCT, especially in eyes with occult lesions, is suggested if one is interested in pursuing a non-fixed, anti-VEGF dosing regimen that will result in visual acuity outcomes similar to those seen with fixed dosing.

The current analysis has several strengths. First, it was based on data from two large, prospective, randomised, controlled clinical trials, which resulted in relatively large sample sizes in each leakage/retinal fluid subgroup. Second, all imaging procedures were undertaken in accordance with a standardised protocol, and the images were evaluated by independent, masked reading centres, limiting the likelihood of bias. However, this analysis is limited by the fact that it was conducted post hoc. Furthermore, FA was only performed every 6 months, limiting our overall understanding of its ability to guide treatment decisions. Additionally, TD-OCTs were utilised rather than the currently more commonly used spectral domain-OCTs. Finally, CNV lesion types were categorised using the standard angiographic classification at the time of the studies: PC, MC and occult.

In summary, the results from this post hoc analysis demonstrate that fixed dosing with an anti-VEGF agent over 1 year has a cumulative, beneficial effect, with the majority of eyes having no evidence of disease activity (as evaluated by both leakage and retinal fluid status) at week 52. Moreover, the data reveal a relationship between the established functional benefits of anti-VEGF treatment (improved visual acuity) with a previously under-recognised anatomic effect (improving retinal dryness) of fixed anti-VEGF dosing strategies versus OCT-guided treatment strategies. Both functional and anatomic data should be considered when choosing an anti-VEGF dosing regimen for the treatment of patients with nAMD.

Acknowledgments

Editorial assistance was provided by Tiffany DeSimone, PhD, of Prime, New York, NY, USA, according to Good Publication Practice guidelines.

References

Footnotes

  • Contributors All authors contributed to the design of this post hoc analysis, data acquisition/research execution, data analysis/interpretation and manuscript preparation. The authors were responsible for all content and editorial decisions.

  • Funding VIEW 1 and VIEW 2 were funded by Regeneron Pharmaceuticals, Inc., Tarrytown, New York, and Bayer HealthCare, Berlin, Germany. The sponsors participated in the design and conduct of these studies, analysis of the data and preparation of this manuscript.

  • Competing interests DMM has the following disclosures: 1800 Contacts (Board of Directors, equity), Akebia (Consulting for ROP), Alcon (Data Safety Monitoring Board), Allegro (SAB), Apellis (Site PI), Bayer (ROP Imaging Committee), Congruence Medical Solutions (Consultant), dSentz (Founder, Board of Directors, equity), Iconic Therapeutics (Steering Committee), Irenix (SAB), Grand Legend Technology (Equity), Linc (Founder, Equity, Board of Directors), Novartis (Data Safety Monitoring Board), Pr3vent (Founder, Board of Directors, equity), Prime (CME consultant), Promisight (Founder, Board of Directors, equity), Pykus (SAB, equity), Regeneron (CME consultant, ROP Steering Committee), Shapiro Law (ROP expert witness), Versl (Founder, equity), Vindico (CME consultant), Visunex Medical Systems, Co (SAB, equity). DT and NS were salaried employees of Regeneron Pharmaceuticals, Inc. at the time that these analyses were undertaken. Both are paid consultants to Regeneron Pharmaceuticals, Inc. NS also serves as a consultant to Aerie, Allegro, Apellis, Adverum, RegenexBio, and SamaCare and is an equity owner in Allegro, Pr3vent, and SamaCare.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.